Experimental evidence indicates that developmental exposure to polybrominated diphenyl ethers (PBDEs) disrupts thyroid hormone function and is neurotoxic, leading to deficits in learning and behavior. A small number of epidemiologic studies, each with significant limitations, similarly suggest but do not confirm these associations These relationships have yet to be tested in a human study that can 1) examine the longitudinal impact of PBDE exposure on cognitive and behavioral outcomes throughout the window of brain development (from gestation through adolescence); and 2) determine the impact of PBDE exposure on thyroid hormones as an independent effect or mediator of PBDE-induced neurotoxicity throughout childhood. The central hypothesis to be tested in this application is that both prenatal and postnatal exposure to PBDEs alters circulating thyroid hormones during childhood, thereby influencing cognitive and behavioral developmental indices. We will evaluate this hypothesis within the existing infrastructure of the Columbia Center for Children's Environmental Health's longitudinal birth cohort study. This study has characterized the chemical and social environments of 350 children, residing in inner-city communities of New York City, from birth through age 12 and has conducted detailed assessments of child cognition, behavior, and thyroid hormone status longitudinally throughout childhood. By measuring PBDEs in peripheral blood collected at three developmental time points (birth, ages 2-3, and 5-7 years), we will pursue the following specific aims in children at ages 3-5, 7- 9, and 10-11: 1) determine whether PBDE exposure affects child cognitive development (including learning, working memory and spatial memory); 2) evaluate whether PBDE exposure affects child behavior (including hyperactivity, attention and social problems); and 3) assess whether PBDE exposure affects thyroid function and if thyroid hormone disruption mediates associations between PBDE exposure and child cognitive development and behavior. The proposed research is innovative because it fills several important gaps in the existing epidemiologic literature that have thus far impeded our ability to characterize the longitudinal impact of PBDE exposure occurring throughout childhood on neurodevelopment over time. By evaluating the neurotoxic effects of both pre- and postnatal PBDE exposure in a large, U.S.-based longitudinal cohort study, this study will provide a fingerprint of PBDE-induced neurotoxicity in humans, supplying evidence that will implicate or refute the role of thyroid hormone disruption. While the production of all PBDE-containing products is slated to be phased out in the U.S. as of 2013, we anticipate that due to its persistence, PBDE exposure will continue for many years thereafter through residential and dietary reservoirs. Understanding the PBDE fingerprint will allow us to readily distinguish its effects from other potentially neurotoxic environmental exposures. This information will inform the urgent and ongoing policy debate about how best to regulate these and other ubiquitous environmental pollutants. PUBLIC HEALTH RELEVANCE: The etiology of neurodevelopmental disorders is likely the result of complex interactions of genetic, social, and environmental factors. This proposal will address the critical research questions of whether, when and how early-life exposure to the neurotoxic flame retardants polybrominated diphenyl ethers (PBDEs) affect child cognitive development and behavior. While early intervention may mitigate the substantial individual and societal impact of neurodevelopmental disabilities, understanding the etiology can lead to preventive strategies that will be more effective in the long-term.